Background: Activating mutation in the MAPK pathway drive malignant transformation in melanoma, with BRAF and NRAS being the most common driver mutations, which occurs in over 50% and 20% of melanoma. Patient with BRAF mutant melanoma treated with MEK and BRAF inhibitors (MEKi and BRAFi) have extended overall survival. However, the inhibitors initially effective, but it triggers the resistance to the targeted therapies. In addition to BRAF and NRAS, the next most frequently observed somatic protein -coding hotspot mutation in melanoma is the RAC1c.85C>T single nucleotide variant ending the p29S amino acid changes found 9% of melanoma. RAC1 p29S mutation remain oncogenic and biochemically active in melanoma. We are investigating the molecular mechanism of RAC signaling and cancer metastasis, and functional role of RAC1p29S mutation and in resistance to ERK/MEK inhibitors by maintaining the MAPK signaling pathways using genetically engineered mice. The biology of aging process that promotes the conversion of normal self-renewing cell into dysfunctional cancer cells using genetically engineered mice. Although mice rarely develop melanoma spontaneously but can do so when genetically modified to carry defined mutations that mic have the genetic lesions found in human melanomas. We are maintaining mice with genetic modifications, RAC1P29S mice in C57/BL6 background and crossing with mice that carry Tyr::CreER: BRAFCA;PTENlox/lox (PBT) that carry a tamoxifeninducible Crerecombinase under the control of a probable ABC transporter ATP-binding protein and, P16tdTomato, p16 INK4 the conditional knock-in mouse model, p16-floxed, contains loxP sites in the Cdkn2a gene. This strain can be crossed to the loxP-stop-loxPtdTomato reported mouse (Gt(ROSA)26Sortm14-CAG-tdTomato) Hze) Cre-expressing strains to investigate how the loss of p16INK4a affects early oncogenesis and senescence in melanoma. We hope that RAC1P29S status in melanoma may an important predictor for BRAFi and MEKi resistance in patients, and consequently should be assess as a predictive biomarker to such therapies in the clinic.